Imidazopyrazinones as GABA-A receptor anxiolytics

ABSTRACT

The present invention discloses a compound of formula I, or a pharmaceutically acceptable salt thereof: (I) wherein —U—V— represents —CH═CH—, or —CH 2 —CH 2 —, —N═CH— or —CH═N—; X 1  represents hydrogen, halogen, C 1-6  alkyl, trifluoromethyl or C 1-6  alkoxy; X 2  represents hydrogen or halogen; Y represents a chemical bond, an oxygen atom, or a —NH— or —OCH 2 — linkage; Z represents an optionally substituted aryl or heteroaryl group; R 1  represents hydrocarbon, a heterocyclic group, trifluoromethyl, —SO 2 R a , —SO 2 NR a R b , —COR a , —CO 2 R a  or —CONR a R b ; and R a  and R b  independently represent hydrogen, hydrocarbon or a heterocyclic group; pharmaceutical compositions comprising it; its use in methods of treatment; use of it in the manufacture of a medicament for treating and/or preventing anxiety; convulsions or a cognitive disorder; and methods of treatment using it.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/GB2003/004685, filed Oct. 29, 2003, whichclaims priority under 35 U.S.C. § 119 from GB Application No. 0225923.2,filed Nov. 6, 2002, GB Application No. 0302529.3, filed Feb. 4, 2003, GBApplication No. 0304415.3, filed Feb. 26, 2003 and GB Application0313646.2, filed Jun. 12, 2003.

The present invention relates to classes of substitutedimidazo-pyrazinone derivatives, substituted imidazotriazine derivativesand purinone derivatives and to their use in therapy. More particularly,this invention is concerned with imidazo[1,2-a]pyrazin-8-one analoguesand imidazo[1,2-d]triazin-8-one analogues which are substituted in the3-position by a substituted phenyl ring, and with purin-6-one analogueswhich are substituted in the 9-position by a substituted phenyl ring.These compounds are ligands for GABA_(A) receptors and are thereforeuseful in the therapy of deleterious neurological complaints.

A description of the theoretical background underlying this inventioncan be found on pages 1-5 of WO-A-02074773 (Merck Sharp & Dohme Ltd.).

WO 02/10170 describes a class of 3-phenylimidazo[1,2-a]pyrazinederivatives which are stated to be selective ligands for GABA_(A)receptors, in particular having high affinity for the α2 and/or α3subunit thereof, and accordingly to be of benefit in the treatmentand/or prevention of neurological disorders, including anxiety andconvulsions. However, there is no disclosure nor any suggestion in thatpublication of therapeutic agents based on a 7-substitutedimidazo[1,2-a]pyrazin-8-one ring system.

The present invention provides a compound of formula I, or apharmaceutically acceptable salt thereof:

wherein

—U—V— represents —CH═CH—, or —CH₂—CH₂—, —N═CH— or —CH═N—;

X¹ represents hydrogen, halogen, C₁₋₆ alkyl trifluoromethyl or C₁₋₆alkoxy;

X² represents hydrogen or halogen;

Y represents a chemical bond, an oxygen atom, or a —NH— or —OCH₂—linkage;

Z represents an optionally substituted aryl or heteroaryl group;

R¹ represents hydrocarbon, a heterocyclic group, trifluoromethyl,—SO₂R^(a), —SO₂NR^(a)R^(b), —COR^(a), —CO₂R^(a) or —CONR^(a)R^(b); and

R^(a) and R^(b) independently represent hydrogen, hydrocarbon or aheterocyclic group.

The present invention also provides a compound of formula I as depictedabove, or a pharmaceutically acceptable salt thereof, wherein

—U—V— represents —CH═CH—;

Y represents a chemical bond, an oxygen atom, or a —NH— linkage; and

X¹, X², Z and R¹ are as defined above.

Definitions of the aryl or heteroaryl group Z, pharmaceuticallyacceptable salts of the compounds, the terms “hydrocarbon” and “aheterocyclic group” as used herein, suitable alkyl, alkenyl, alkynyl,and cycloalkyl groups, typical examples of C₃₋₇ cycloalkyl(C₁₋₆)alkylgroups, particular indanyl, aryl and aryl(C₁₋₆)alkyl groups, suitableheterocycloalkyl and heteroaryl groups, the expression“heteroaryl(C₁₋₆)alkyl”, optional substituents on the hydrocarbon andheterocyclic groups and the term “halogen” as used herein can be foundon columns 3-5 of U.S. Pat. No. 6,900,215.

General comments about stereochemistry can be found on column 5 of U.S.Pat. No. 6,900,215.

In one embodiment of the compounds according to the present invention,—U—V— represents —CH═CH—.

In another embodiment, —U—V— represents —CH₂—CH₂—.

Suitable values for the X¹ substituent include hydrogen, fluoro, chloro,methyl, trifluoromethyl and methoxy; in particular hydrogen or fluoro;and especially fluoro.

Suitably, X¹ represents halogen, C₁₋₆ alkyl, trifluoromethyl or C₁₋₆alkoxy. Typical values of X¹ include fluoro, chloro, methyl,trifluoromethyl and methoxy, especially fluoro.

Typical values of X² include hydrogen and fluoro, especially hydrogen.

In a preferred embodiment, Y represents a chemical bond.

In an alternative embodiment, Y represents a —OCH₂— linkage.

In another embodiment, Y represents an oxygen atom.

In a further embodiment, Y represents a —NH— linkage.

Selected values for the substituent Z include phenyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl oxazolyl,isoxazolyl, thiazolyl, isothiazolyl pyrrolyl, pyrazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl, any of which groupsmay be optionally substituted by one or more substituents.

Particular values of Z include phenyl and triazolyl, either of whichgroups may be optionally substituted by one or more substituents.

In one favoured embodiment, Z represents an optionally substitutedphenyl group, in particular monosubstituted or disubstituted phenyl. Inanother favoured embodiment, Z represents optionally substitutedpyridinyl, especially unsubstituted, monosubstituted or disubstitutedpyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

Examples of suitable substituents on the group Z include fluoro, chloro,cyano, nitro, methyl, hydroxy, methoxy, oxy, methanesulphonyl, amino,aminocarbonyl, formyl, methoxycarbonyl and —CH═NOH.

Examples of typical substituents on the group Z include fluoro, chloro,cyano and methyl.

Examples of particular substituents on the group Z include fluoro andcyano, especially cyano.

Detailed values of Z include cyanophenyl (cyano)(fluoro)phenyl,(chloro)(cyano)phenyl, nitrophenyl, methoxyphenyl,methanesulphonyl-phenyl, pyridinyl, fluoro-pyridinyl,difluoro-pyridinyl, (amino)(chloro)pyridinyl, cyano-pyridinylmethyl-pyridinyl, hydroxy-pyridinyl methoxy-pyridinyl oxy-pyridinyl,aminocarbonyl-pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,cyano-thienyl, aminocarbonyl-thienyl, formyl-thienyl,methoxycarbonyl-thienyl, thienyl-CH═NOH, thiazolyl isothiazolyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl and methyl-tetrazolyl.Additionally, Z may represent methyl-triazolyl.

Specific values of Z include cyanophenyl, (cyano)(fluoro)phenyl,pyridinyl, difluoro-pyridinyl and cyano-pyridinyl.

Individual values of Z include cyanophenyl, (cyano)fluoro)phenyl,(chloro)(cyano)phenyl and methyl-triazolyl.

In one embodiment, Z represents cyanophenyl, especially 2-cyanophenyl.

In another embodiment, Z represents (cyano)(fluoro)phenyl, especially2-cyano-4-fluorophenyl. Alternative aspects of this embodiment include2-cyano-5-fluorophenyl, 2-cyano-6-fluorophenyl and4-cyano-2-fluorophenyl.

In an additional embodiment, Z represents (chloro)(cyano)phenyl,especially 3-chloro-4-cyanophenyl.

In a further embodiment, Z represents methyl-triazolyl, especially1-methyl-1H-[1,2,3]triazol-4-yl or 2-methyl-2H-[1,2,4]triazol-3-yl.

Typically, R¹ represents hydrocarbon, a heterocyclic group,trifluoromethyl, —COR^(a) or —CO₂R^(a).

Typical values of R^(a) include hydrogen and C₁₋₆ alkyl. Suitably, R^(a)represents hydrogen or methyl.

Typical values of R^(b) include hydrogen, C₁₋₆ alkyl, hydroxy(C₁₋₆)alkyland di(C₁₋₆)alkylamino(C₁₋₆)alkyl. Suitably, R^(b) represents hydrogen,methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values ofR^(b) include hydrogen, hydroxyethyl and dimethylaminoethyl, especiallyhydrogen or dimethylaminoethyl.

Suitable values of R¹ include C₁₋₆ alkyl, halo(C₁₋₆)alkyl,dihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, dihydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy(C₁₋₆)alkyl di(C₁₋₆)alkoxy(C₁₋₆)alkyl, cyano(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl C₃₋₇ cycloalkyl, heteroaryl, C₁₋₆alkyl-heteroaryl, heteroaryl(C₁₋₆)alkyl, trifluoromethyl, formyl, C₂₋₆alkylcarbonyl and C₂₋₆ alkoxycarbonyl. Additional values of R¹ includetrihalo(C₁₋₆)alkyl and (C₁₋₆)alkyl-heteroaryl(C₁₋₆)alkyl.

Representative values of R¹ include C₁₋₆ alkyl, halo(C₁₋₆)alkyl,dihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl and trifluoromethyl.

Particular values of R¹ include C₁₋₆ alkyl, halo(C₁₋₆)alkyl,dihalo(C₁₋₆)alkyl, trihalo(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl and(C₁₋₆)alkyl-heteroaryl(C₁₋₆)alkyl.

Individual values of R¹ include methyl, ethyl, fluoromethyl,difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl,hydroxyethyl (especially 2-hydroxyethyl), fluoroethyl (especially2-fluoroethyl), difluoroethyl (especially 2,2-difluoroethyl),dimethoxyethyl (especially 2,2-dimethoxyethyl), isopropyl, hydroxypropyl(especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially1,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl),cyanopropyl (especially 2-cyanoprop-2-yl), methoxycarbonylpropyl(especially 2-methoxycarbonylprop-2-yl), tert-butyl, hydroxybutyl(especially 1-hydroxy-2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl,thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl,triazolylmethyl, trifluoromethyl, formyl, acetyl and methoxycarbonyl.Additional values of R¹ include trifluoroethyl (especially2,2,2-trifluoroethyl), methyl-triazolylmethyl (especially2-methyl-2H-[1,2,4]triazol-3-ylmethyl) and pyridinylmethyl (especiallypyridin-2-ylmethyl).

Specific values of R¹ include methyl, ethyl, fluoroethyl (especially2-fluoroethyl), difluoroethyl (especially 2,2-difluoroethyl),trifluoroethyl (especially 2,2,2-trifluoroethyl), isopropyl,methyl-triazolylmethyl (especially2-methyl-2H-[1,2,4]triazol-3-ylmethyl) and pyridinylmethyl (especiallypyridin-2-ylmethyl).

In a first embodiment, R¹ represents methyl. In a second embodiment, R¹represents ethyl. In a third embodiment, R¹ represents fluoroethyl(especially 2-fluoroethyl). In a fourth embodiment, R¹ representsdifluoroethyl (especially 2,2-difluoroethyl). In a fifth embodiment, R¹represents trifluoroethyl (especially 2,2,2-trifluoroethyl). In a sixthembodiment, R¹ represents isopropyl. In a seventh embodiment, R¹represents methyl-triazolylmethyl (especially2-methyl-2H-[1,2,4]triazol-3-ylmethyl). In an eighth embodiment, R¹represents pyridinylmethyl (especially pyridin-2-ylmethyl). In afavoured embodiment, R¹ represents 2-hydroxyprop-2-yl. In anotherembodiment, R¹ represents 2-fluoroprop-2-yl. In an additionalembodiment, R¹ represents trifluoromethyl.

In one embodiment individual values of R¹ when —U—V— is —N═CH— or —CH═N—include methyl, ethyl, fluoromethyl, difluoromethyl, methoxymethyl,dimethoxymethyl, hydroxyethyl (especially 2-hydroxyethyl), fluoroethyl(especially 2-fluoroethyl), difluoroethyl (especially2,2-difluoroethyl), dimethoxyethyl (especially 2,2-dimethoxyethyl),isopropyl, hydroxypropyl, dihydroxypropyl (especially1,2-dihydroxyprop-2-yl), cyanopropyl, methoxycarbonylpropyl (especially2-methoxycarbonylprop-2-yl), tert-butyl, hydroxybutyl (especially1-hydroxy-2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl, thienyloxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl,triazolylmethyl, trifluoromethyl, formyl, acetyl and methoxycarbonyl.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and pharmaceuticallyacceptable salts thereof:

wherein

U, V and Z are as defined above;

X¹¹ represents hydrogen, fluoro, chloro, methyl, trifluoromethyl ormethoxy;

X¹² represents hydrogen or fluoro; and

R¹¹ represents C₁₋₆ alkyl, halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl,trihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, dihydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy(C₁₋₆)alkyl, di(C₁₋₆)alkoxy(C₁₋₆)alkyl, cyano(C₁₋₆)alkyl C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, heteroaryl, C₁₋₆alkyl-heteroaryl heteroaryl(C₁₋₆)alkyl,(C₁₋₆)allyl-heteroaryl(C₁₋₆)allyl, trifluoromethyl, formyl, C₂₋₆alkylcarbonyl or C₂₋₆ alkoxycarbonyl.

The present invention also provides a compound of formula IIA asdepicted above, or a pharmaceutically acceptable salt thereof, wherein

—U—V— represents —CH═CH—;

R¹¹ represents C₁₋₆ alkyl, halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, dihydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl,di(C₁₋₆)alkoxy(C₁₋₆)alkyl, cyano(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, heteroaryl, C₁₋₆alkyl-heteroaryl, heteroaryl(C₁₋₆)alkyl, trifluoromethyl, formyl, C₂₋₆alkylcarbonyl or C₂₋₆ alkoxycarbonyl; and

Z, X¹¹ and X¹² are as defined above.

Suitable values of X¹¹ include hydrogen and fluoro, especially fluoro.

Typical values of X¹¹ include fluoro, chloro, methyl, trifluoromethyland methoxy.

A particular value of X¹¹ is fluoro.

In a favoured embodiment, X¹² represents hydrogen. In anotherembodiment, X¹² represents fluoro.

Where R¹¹ represents heteroaryl, this group is suitably pyridinyl,furyl, thienyl or oxazolyl.

Where R¹¹ represents C₁₋₆ alkyl-heteroaryl, this group is suitablymethylthiazolyl (e.g. 2-methylthiazol-5-yl) or methyloxadiazolyl (e.g.3-methyl-[1,2,4]oxadiazol-5-yl).

Where R¹¹ represents heteroaryl(C₁₋₆)alkyl, this group is suitablyimidazolylmethyl or triazolylmethyl. Additionally, theheteroaryl(C₁₋₆)alkyl group R¹¹ may be pyridinylmethyl.

Representative values of R¹¹ include C₁₋₆ alkyl, halo(C₁₋₆)alkyldihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl and trifluoromethyl.

Particular values of R¹¹ include C₁₋₆ alkyl, halo(C₁₋₆)alkyl,dihalo(C₁₋₆)alkyl, trihalo(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl and(C₁₋₆)alkyl-heteroaryl(C₁₋₆)alkyl.

Individual values of R¹¹ include methyl, ethyl, fluoromethyl,difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl,hydroxyethyl (especially 2-hydroxyethyl), fluoroethyl (especially2-fluoroethyl), difluoroethyl (especially 2,2-difluoroethyl),dimethoxyethyl (especially 2,2-dimethoxyethyl), isopropyl, hydroxypropyl(especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially1,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl),cyanopropyl (especially 2-cyanoprop-2-yl), methoxycarbonylpropyl(especially 2-methoxycarbonylprop-2-yl), tert-butyl, hydroxybutyl(especially 1-hydroxy-2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl,thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl,triazolylmethyl, trifluoromethyl, formyl, acetyl and methoxycarbonyl.Additional values of R¹¹ include trifluoroethyl (especially2,2,2-trifluoroethyl), methyl-triazolylmethyl (especially2-methyl-2H-[1,2,4]triazol-3-ylmethyl) and pyridinylmethyl (especiallypyridin-2-ylmethyl).

Specific values of R¹¹ include methyl, ethyl, fluoroethyl (especially2-fluoroethyl), difluoroethyl (especially 2,2-difluoroethyl),trifluoroethyl (especially 2,2,2-trifluoroethyl), isopropyl,methyl-triazolylmethyl (especially2-methyl-2H-[1,2,4]triazol-3-ylmethyl) and pyridinylmethyl (especiallypyridin-2-ylmethyl).

In a first embodiment, R¹¹ represents methyl. In a second embodiment,R¹¹ represents ethyl. In a third embodiment, R¹¹ represents fluoroethyl(especially 2-fluoroethyl). In a fourth embodiment, R¹¹ representsdifluoroethyl (especially 2,2-difluoroethyl). In a fifth embodiment, R¹¹represents trifluoroethyl (especially 2,2,2-trifluoroethyl). In a sixthembodiment, R¹¹ represents isopropyl. In a seventh embodiment, R¹¹represents methyl-triazolylmethyl (especially2-methyl-2H-[1,2,4]triazol-3-ylmethyl). In an eighth embodiment, R¹¹represents pyridinylmethyl (especially pyridin-2-ylmethyl). In afavoured embodiment, R¹¹ represents 2-hydroxyprop-2-yl. In anotherembodiment, R¹¹ represents 2-fluoroprop-2-yl. In an additionalembodiment, R¹¹ represents trifluoromethyl.

When —U—V— is —N═CH— or —CH═N— individual values of R¹¹ include methyl,ethyl fluoromethyl, difluoromethyl, methoxymethyl, dimethoxymethyl,hydroxyethyl (especially 2-hydroxyethyl), fluoroethyl (especially2-fluoroethyl), difluoroethyl (especially 2,2-difluoroethyl),dimethoxyethyl (especially 2,2-dimethoxyethyl), isopropyl,hydroxypropyl, dihydroxypropyl (especially 1,2-dihydroxyprop-2-yl),cyanopropyl, methoxycarbonylpropyl (especially2-methoxycarbonylprop-2-yl), tert-butyl, hydroxybutyl (especially1-hydroxy-2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl, thienyl,oxazolyl, methylthiazolyl methyloxadiazolyl imidazolylmethyl,triazolylmethyl, trifluoromethyl, formyl, acetyl and methoxycarbonyl.

One representative subset of the compounds of formula IIA above isrepresented by the compounds of formula IIB, and pharmaceuticallyacceptable salts thereof:

wherein U, V, X¹¹, X¹² and R¹¹ are as defined above; and

R² represents hydrogen or fluoro.

In one embodiment, R² is hydrogen.

In another embodiment, R² is fluoro, in which case the fluorine atom R²is favourably attached to the phenyl ring at the 4-, 5- or 6-position(relative to the cyano group at position 2).

Another representative subset of the compounds of formula IIA above isrepresented by the compounds of formula IIC, and pharmaceuticallyacceptable salts thereof:

wherein U, V, X¹¹, X¹² and R¹¹ are as defined above; and

R³ represents hydrogen, fluoro, cyano or methyl.

In one embodiment, R³ is hydrogen.

In an additional embodiment, R³ is fluoro.

In another embodiment, R³ is cyano.

In a further embodiment, R³ is methyl.

A further representative subset of the compounds of formula IIA above isrepresented by the compounds of formula IID, and pharmaceuticallyacceptable salts thereof:

wherein U, V, X¹¹, X¹², R³ and R¹¹ are as defined above; and

R⁴ represents hydrogen or fluoro.

Suitably, R⁴ represents hydrogen.

In another embodiment, R⁴ represents fluoro.

The present invention also provides a compound of formula IIB, IIC orIID as depicted above, or a pharmaceutically acceptable salt thereof,wherein

—U—V— represents —CH═CH—; and

X¹¹, X¹², R², R³, R⁴ and R¹¹ are as defined above.

Specific compounds within the scope of the present invention include:

-   2′-fluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;-   5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-2′-fluorobiphenyl-2-carbonitrile;-   2′-fluoro-5′-[7-(2-fluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;-   5′-[7-(2,2-difluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]-2′-fluorobiphenyl-2-carbonitrile;-   4,2′-difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;-   4,2′-difluoro-5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;-   4,2′-difluoro-5′-[7-(2,2-difluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;-   4,2′-difluoro-5′-[7-(1-methylethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;-   3-chloro-2′-fluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-4-carbonitrile;-   4,2′-difluoro-5′-[7-(2-fluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;-   4′-fluoro-3′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;-   5′-fluoro-3′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;-   2,2′-difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-4-carbonitrile;-   4,2′-difluoro-5′-[7-(2,2,2-trifluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;-   4,2′-difluoro-5′-[7-(2-methyl-2H-[1,2,4]triazol-3-ylmethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;-   3-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one;-   3-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one;-   7-ethyl-3-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7H-imidazo[1,2-a]pyrazin-8-one;-   4,2′-difluoro-5′-[8-oxo-7-(pyridin-2-ylmethyl)-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;-   4,2′-difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;-   4,2′-difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;-   5,2′-difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;-   6,2′-difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;-   6,2′-difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;-   6,2′-difluoro-5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;-   5,2′-difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;-   4,2′-difluoro-5′-[8-oxo-7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;-   6,2′-difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;    and pharmaceutically acceptable salts thereof

Also provided is:

-   4,2′-difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-d][1,2,4]triazin-3-yl)biphenyl-2-carbonitrile;    and pharmaceutically acceptable salts thereof.

Also provided is:

-   3′-(1-methyl-6-oxo-1,6-dihydropurin-9-yl)biphenyl-2-carbonitrile;    and pharmaceutically acceptable salts thereof.

Also provided by the present invention is a method for the treatmentand/or prevention of anxiety which comprises administering to a patientin need of such treatment an effective amount of a compound of formula Ias defined above or a pharmaceutically acceptable salt thereof.

Further provided by the present invention is a method for the treatmentand/or prevention of convulsions (e.g. in a patient suffering fromepilepsy or a related disorder) which comprises administering to apatient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable saltthereof.

Details of the binding affinity of the claimed compounds, theirpotentation of the GABA EC₂₀ response, measurement of anxiolytic andanticonvulsant activity, and pharmaceutical compositions can be found onpages 27-30 of WO-A-02074773.

In another aspect, the present invention provides a method for thetreatment and/or prevention of cognitive disorders, including dementingconditions such as Alzheimer's disease, which comprises administering toa patient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable saltthereof.

Cognitive disorders for which the compounds of the present invention maybe of benefit include delirium, dementia, amnestic disorders, andcognition deficits, including age-related memory deficits, due totraumatic injury, stroke, Parkinson's disease and Down Syndrome. Any ofthese conditions may be attributable to substance abuse or withdrawal.Examples of dementia include dementia of the Alzheimer's type with earlyor late onset, and vascular dementia, any of which may be uncomplicatedor accompanied by delirium, delusions or depressed mood; and dementiadue to HIV disease, head trauma, Parkinson's disease or Creutzfeld-Jakobdisease.

In order to elicit their behavioural effects, the compounds of theinvention will ideally be brain-penetrant; in other words, thesecompounds will be capable of crossing the so-called “blood-brainbarrier”. Preferably, the compounds of the invention will be capable ofexerting their beneficial therapeutic action following administration bythe oral route.

Unit dosage forms comprising the claimed compounds contain from 0.1 toabout 500 mg of the active ingredient of the present invention. Typicalunit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25,50 or 100 mg, of the active ingredient.

In the treatment of neurological disorders, a suitable dosage level isabout 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg perday, and especially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds in accordance with the present invention may be preparedby a process which comprises attachment of the R¹ moiety to a compoundof formula III:

wherein U, V, X¹, X², Y and Z are as defined above; by conventionalalkylation or acylation methods.

For instance, where R¹ in the compounds of formula I above represents anoptionally substituted C₁₋₆ alkyl group, the moiety R¹ may be attachedby treating the appropriate compound of formula III with a suitablealkyl halide, e.g. iodomethane, iodoethane, 1-bromo-2-fluoroethane,2-bromo-1,1-difluoroethane, 1-iodo-2,2,2-trifluoroethane or2-bromopropane, typically in the presence of a base such as sodiumhydride. Similarly, where R¹ represents an optionally substitutedheteroaryl(C₁₋₆)alkyl group, the moiety R¹ may be attached by reactingthe appropriate compound of formula III with a suitable alkylatingagent, e.g. 3-chloromethyl-2-methyl-2H-[1,2,4]triazole or2-chloromethylpyridine, typically in the presence of a base such assodium hydride. Alternatively, where R¹ in the compounds of formula Iabove represents methyl, the methyl group R¹ may be attached by treatingthe appropriate compound of formula III with a strong base such ashexamethyldisilazane, followed by chloro(chloromethyl)dimethylsilane;and subsequently treating the compound thereby obtained with cesiumfluoride.

Except where X¹ and X² both simultaneously represent hydrogen, thecompounds of formula III above are novel compounds and represent afurther feature of the present invention.

The compounds of formula III may suitably be prepared from theappropriate methoxy-substituted compound of formula IV:

wherein U, V, X¹, X², Y and Z are as defined above; by treatment withhydrogen bromide, typically in acetic acid.

In another procedure, the compounds in accordance with the presentinvention may be prepared by a process which comprises reacting acompound of formula V with a compound of formula VI:

wherein U, V, X¹, X², Y, Z and R¹ are as defined above, L¹ represents asuitable leaving group, and M¹ represents a boronic acid moiety —B(OH)₂or a cyclic ester thereof formed with an organic diol, e.g. pinacol,1,3-propanediol or neopentyl glycol, or M¹ represents —Sn(Alk)₃ in whichAlk represents a C₁₋₆ alkyl group, typically n-butyl; in the presence ofa transition metal catalyst.

The leaving group L¹ is typically a halogen atom, e.g. bromo.

The transition metal catalyst of use in the reaction between compounds Vand VI is suitably palladium(II) acetate, in which case the reaction istypically accomplished in the presence of triphenylphosphine. Thereaction is conveniently carried out at an elevated temperature in asolvent such as 1,4-dioxane, typically in the presence of sodiumcarbonate.

The intermediates of formula V may be prepared by attaching the R¹moiety to a compound of formula VII:

wherein U, V and L¹ are as defined above; under conditions analogous tothose described above for attachment of the R¹ moiety to a compound offormula III.

The intermediates of formula VII may be prepared from the appropriatemethoxy-substituted precursor of formula VIII:

wherein U, V and L¹ are as defined above; by treatment with hydrogenbromide, typically in acetic acid.

In a further procedure, the compounds in accordance with the presentinvention may be prepared by a process which comprises reacting acompound of formula IX with a compound of formula X:

wherein U, V, X¹, X², Y, Z, R¹ and L¹ are as defined above; in thepresence of a transition metal catalyst.

The transition metal catalyst of use in the reaction between compoundsIX and X is suitably palladium(II) acetate, in which case the reactionis typically accomplished in the presence of triphenylphosphine. Thereaction is conveniently carried out at an elevated temperature in asolvent such as N,N-dimethylacetamide, typically in the presence ofpotassium acetate.

The intermediates of formula IX where —U—V— is —N═C— may suitably beprepared by attachment of the R¹ moiety to the compound of formula XI:

by conventional alkylation or acylation methods.

For instance, where R¹ in the compounds of formula I above represents anoptionally substituted C₁₋₆ alkyl group, the moiety R¹ may be attachedby treating the appropriate compound of formula IX with a suitable alkylhalide, e.g. iodomethane, iodoethane, 1-bromo-2-fluoroethane or2-bromo-1,1-difluoroethane, typically in the presence of a base such assodium hydride. Alternatively, where R¹ in the compounds of formula Iabove represents methyl, the methyl group R¹ may be attached by treatingthe appropriate compound of formula IX with a strong base such ashexamethyldisilazane, followed by chloro(chloromethyl)-dimethylsilane;and subsequently treating the compound thereby obtained with cesiumfluoride.

The intermediate of formula XI may be prepared by reacting the compoundof formula XII:

with N,N-dimethylformamide dimethyl acetal, typically by heating inDowtherm A.

The intermediate of formula XII may be obtained from the processdescribed in EP-A-0713876.

The compounds in accordance with the present invention particularlythose in which —U—V— is —CH═N—, may alternatively be prepared by aprocess which comprises reacting a compound of formula XIII:

wherein U, V, X¹, X², Y, Z and R¹ are as defined above; with formicacid.

The reaction is conveniently accomplished by stirring the reactants atan elevated temperature, typically at the reflux temperature of thereaction mixture.

The intermediates of formula XIII may be prepared by reduction of acompound of formula XIV:

wherein U, V, X¹, X², Y, Z and R¹ are as defined above.

The reduction is conveniently effected by treating compound XIV with areducing agent, e.g. tin(II) chloride, typically at an elevatedtemperature in a suitable solvent, for example a mixture of ethanol andtetrahydrofuran.

The intermediates of formula XIV may be prepared by reacting a compoundof formula XV with a compound of formula XVI:

wherein U, V, X¹, X², Y, Z and R¹ are as defined above, and L¹represents a suitable leaving group.

The leaving group L¹ is typically a halogen atom, e.g. chloro.

The reaction between compounds XV and XVI is conveniently effected byheating the reactants, to a temperature typically in the region of 90°C., in the presence of a base such as triethylamine, in a solvent suchas dimethylsulfoxide.

In another procedure, the compounds according to the present invention,particularly those in which —U—V— is —CH═N—, in which Y represents achemical bond may be prepared by a process which comprises reacting acompound of formula XVII with a compound of formula XVIII:

wherein U, V, X¹, X², Z and R¹ are as defined above, L² represents asuitable leaving group, and M¹ represents a boronic acid moiety —B(OH)₂or a cyclic ester thereof formed with an organic diol, e.g. pinacol,1,3-propanediol or neopentyl glycol, or M¹ represents —Sn(Alk)₃ in whichAlk represents a C₁₋₆ alkyl group, typically n-butyl; in the presence ofa transition metal catalyst.

In the compounds of formula XVII above, the leaving group L² istypically trifluoromethanesulfonyloxy (triflyloxy); or a halogen atom,e.g. bromo.

The transition metal catalyst of use in the reaction between compoundsXVII and XVIII is suitably tetrakis(triphenylphosphine)-palladium(0).The reaction is conveniently carried out at an elevated temperature in asolvent such as N,N-dimethylacetamide, 1,2-dimethoxyethane, 1,4-dioxaneor tetrahydrofuran, advantageously in the presence of potassiumphosphate, copper(I) iodide, sodium carbonate or cesium carbonate.Alternatively, the transition metal catalyst employed may betris(dibenzylideneacetone)dipalladium(0), in which case the reaction isconveniently effected at an elevated temperature in a solvent such as1,4-dioxane, typically in the presence of tri-tert-butylphosphine andpotassium phosphate.

Alternatively, the compounds according to the present invention,particularly those in which —U—V— is —CH═N—, in which Y represents achemical bond may be prepared by a process which comprises reacting acompound of formula XIX with a compound of formula XX:

wherein U, V, X¹, X², Z, R¹, L² and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between compounds XVII and XVIII.

In an additional procedure, the compounds according to the presentinvention, particularly those in which —U—V— is —CH═N—, in which Yrepresents an oxygen atom may be prepared by a process which comprisesreacting a compound of formula XX as defined above with a compound offormula XXI:

wherein U, V, X¹, X² and R¹ are as defined above.

The reaction is conveniently carried out under basic conditions, e.g.using sodium hydride in a solvent such as N,N-dimethylformamide,typically at an elevated temperature which may be in the region of 120°C.

In a further procedure, the compounds according to the presentinvention, particularly those in which —U—V— is —CH═N—, in which Yrepresents a —NH— linkage may be prepared by a process which comprisesreacting a compound of formula XX as defined above with a compound offormula XXII:

wherein U, V, X¹, X² and R¹ are as defined above.

In relation to the reaction between compounds XX and XXII, the leavinggroup L² in the compounds of formula XX may suitably represent fluoro.

The reaction between compounds XX and XXII is conveniently carried outby heating the reactants, typically at a temperature in the region of120° C., in a solvent such as N,N-dimethylformamide.

Where M¹ in the intermediates of formula XVIII and XIX above representsa boronic acid moiety —B(OH)₂ or a cyclic ester thereof formed withpinacol or neopentyl glycol, the relevant compound XVIII or XIX may beprepared by reacting bis(pinacolato)diboron or bis(neopentylglycolato)diborane respectively with a compound of formula XX or XVII asdefined above; in the presence of a transition metal catalyst.

The transition metal catalyst of use in the reaction betweenbis(pinacolato)diboron or bis(neopentyl glycolato)diborane and compoundXX or XVII is suitablydichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium(II). Thereaction is conveniently carried out at an elevated temperature in asolvent such as 1,4-dioxane, optionally in admixture withdimethylsulfoxide, typically in the presence of1,1′-bis(diphenylphosphino)ferrocene and/or potassium acetate.

The intermediates of formula XVII above may be prepared by reacting acompound of formula XXIII:

wherein U, V, X¹, X², R¹ and L² are as defined above; with formic acid;under conditions analogous to those described above for the reactionbetween compound XIII and formic acid.

The intermediates of formula XXIII may be prepared by reaction of acompound of formula V as defined above with a compound of formula XXIV:

wherein X¹, X² and L² are as defined above; under conditions analogousto those described above for the reaction between compounds XV and XVI;followed by reduction of the nitro group in the resulting compound,under conditions analogous to those described above for the reduction ofthe nitro group in compound XIV.

Where L² in the intermediates of formula XVII above representstriflyloxy, the relevant compound XVII may be prepared by reacting theappropriate compound of formula XXI as defined above with triflicanhydride, typically in the presence of pyridine.

The intermediates of formula XXI above may suitably be prepared from theappropriate methoxy-substituted precursor of formula XXV:

wherein U, V, X¹, X² and R¹ are as defined above; by treatment withboron tribromide, typically in chloroform or dichloromethane; or withhydrogen bromide, typically in acetic acid at reflux.

The intermediates of formula XXII and XXV above may be prepared byreacting a compound of formula XV as defined above with the appropriatecompound of formula XXVI:

wherein X¹ and X² are as defined above, and Y¹ represents amino ormethoxy; under conditions analogous to those described above for thereaction between compounds XV and XVI; followed by reduction of thenitro group in the resulting compound, under conditions analogous tothose described above for the reduction of the nitro group in compoundXIV; followed by reaction of the product thereby obtained with formicacid, under conditions analogous to those described above for thereaction between compound XIII and formic acid.

The compounds according to the invention in which Y represents achemical bond and Z represents pyrrol-1-yl may be prepared by reacting acompound of formula XXII as defined above with2,5-dimethoxy-tetrahydrofuran. The reaction is conveniently accomplishedat an elevated temperature in a solvent such as acetic acid.

The intermediates of formula III, IV, V, VII, VIII and IX wherein —U—V—represents —CH₂—CH₂— may be prepared from the corresponding compoundwherein —U—V— represents —CH═CH— by catalytic hydrogenation.

The compounds of formula IV, VI, VIII, IX and X may conveniently beprepared by the procedures described in WO 02/10170, or by methodsanalogous thereto.

Where they are not commercially available, the starting materials offormula XV, XVI, XX, XXIV and XXVI may be prepared by methods analogousto those described in the accompanying Examples, or by standard methodswell known from the art.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art and detailed on pages 40-42 of WO-A-02074773. A compound offormula I wherein —U—V— represents —CH═CH— may be converted into thecorresponding compound wherein —U—V— represents —CH₂—CH₂— by catalytichydrogenation.

Mixtures of products may be purified and intermediates protected asdescribed on pages 42-43 of WO-A-02074773.

The compounds of the accompanying Examples were tested in the assaydescribed on pages 43 and 44 of WO-A-02074773, and all were found topossess a K_(i) value for displacement of [³H]-flumazenil from the α2and/or α3 and/or α5 subunit of the human GABA_(A) receptor of 100 nM orless.

The following Examples illustrate the preparation of compounds accordingto the invention.

EXAMPLE 12′-Fluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile

A suspension of 2,3-dichloropyrazine (35 g, 0.23 mol) in 25% aqueousammonia (200 ml) was heated at 100° C. for 12 h in a PTFE-lined pressurereactor (terminal pressure 100 psi). The reaction was cooled to ambienttemperature and the resulting crystalline solid collected by filtration.This solid was triturated with water (150 ml) and dried to afford2-amino-3-chloropyrazine as a buff-coloured crystalline solid (28 g,92%): δ_(H) (400 MHz, DMSO) 6.78 (2H, br s), 7.56 (1H, d, J 2.5), 7.95(1H, d, J 2.5).

Bromoacetaldehyde diethyl acetal (45 ml, 0.29 mol) was treated withwater (33 ml) and 48% hydrobromic acid (33 ml) and this mixture washeated at 95° C. for 90 min. The reaction was cooled, diluted withpropan-2-ol (300 ml) and treated with sodium hydrogencarbonate (33 g)added in portions. This mixture was stirred for 30 min then filtered.The filtrate was treated with 2-amino-3-chloropyrazine (25 g, 0.19 mol)and then heated at 90° C. for 16 h. The reaction was cooled to ambienttemperature, concentrated to about one-third volume and then treatedwith 48% hydrobromic acid (25 ml). More propan-2-ol (300 ml) was addedand the mixture aged for 1 h. The resulting solid was collected byfiltration, washed with propan-2-ol and then dissolved in water (500ml). This solution was made basic by adding solid sodiumhydrogencarbonate and then extracted with chloroform (3×250 ml). Theorganics were combined, dried over anhydrous magnesium sulphate,filtered and concentrated to give a solid. Trituration with diethylether afforded 8-chloroimidazo[1,2-a]pyrazine as an off-white solid(18.6 g, 63%): δ_(H) (360 MHz, DMSO) 7.73 (1H, d, J 4.5), 7.87 (1H, d, J1), 8.28 (1H, d, J 1), 8.67 (1H, d, J 4.5).

A cooled (0° C.) suspension of 8-chloroimidazo[1,2-a]pyrazine (18.6 g,0.12 mol) and sodium acetate (29.8 g, 0.36 mol) in methanol (125 ml,pre-saturated with solid potassium bromide) was treated with bromine(6.5 ml, 0.13 mol) added dropwise over 5 min. After stirring for 10 minthin-layer chromatography indicated no starting material. Solid sodiumsulphite (15.3 g, 0.12 mol) was then added to the slurry and stirringcontinued for 10 min. The mixture was then treated with saturatedaqueous sodium hydrogencarbonate (650 ml) added in portions. Thismixture was extracted with dichloromethane (2×350 ml). The organics werecombined, dried over anhydrous magnesium sulphate, filtered andconcentrated to afford 3-bromo-8-chloroimidazo[1,2-a]pyrazine as acream-coloured solid: δ_(H) (400 MHz, CDCl₃) 7.82 (1H, d, J 4.5), 7.83(1H, s), 8.05 (1H, d, J 4.6). This solid was suspended in 1:1dichloromethane/methanol (160 ml) and treated with solid sodiummethoxide (9.8 g, 0.18 mol). The resulting mixture was then stirred at40° C. for 2 h. The reaction was cooled, diluted with water (750 ml)then extracted with dichloromethane (600 ml). The organics were driedover anhydrous magnesium sulphate, filtered and concentrated to give3-bromo-8-methoxyimidazo[1,2-a]pyrazine as a white solid (24.5 g, 89%over 2 steps): δ_(H) (360 MHz, DMSO) 4.06 (3H, s), 7.57 (1H, d, J 4.5),7.81 (1H, s), 8.03 (1H, d, J 4.5).

A mixture of the above product (680 mg, 3 mmol) and2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile(prepared as described in WO 02/074773) (1.45 g, 4.5 mmol) intetrahydrofuran (9 ml) was treated with 2M sodium carbonate (3 ml) thendegassed with nitrogen for 10 min.Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) was addedand this mixture was heated under reflux for 12 h. The reaction wascooled and the majority of the solvent removed on a rotary evaporator.The residue was partitioned between dichloromethane and water. Theorganics were washed with water, brine, dried over anhydrous magnesiumsulphate, filtered and concentrated in vacuo. Purification of theresidue by chromatography on silica gel eluting with 2% methanol indichloromethane gave2′-fluoro-5′-(8-methoxyimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrileas a cream solid (768 mg, 74%): δ_(H) (400 MHz, CDCl₃) 4.19 (3H, s),7.38-7.46 (2H, m), 7.53-7.64 (4H, m), 7.71 (1H, td, J 8 and 1.5), 7.73(1H, s), 7.85 (1H, dd, J 8 and 1), 8.02 (1H, d, J 4.5); m/z (ES⁺) 345[M+H]⁺.

A suspension of the above product (750 mg, 2.2 mmol) in hydrogen bromide(30 wt % in acetic acid, 10 ml) was heated at 95° C. for 45 min. Thereaction was cooled, poured into ice water and neutralised by theaddition of solid sodium hydrogencarbonate. The resulting solid wascollected by filtration and air-dried, then triturated with ether, toafford2′-fluoro-5′-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrileas a cream-coloured solid (550 mg, 76%): δ_(H) (360 MHz, DMSO) 6.92 (1H,t, J 6), 7.49 (1H, d, J 5), 7.60-7.71 (2H, m), 7.75-7.89 (5H, m), 8.03(1H, dd, J 7 and 0.5), 11.38 (1H, d, J 5.5); m/z(ES⁺) 331 [M+H]⁺.

A suspension of the above product (250 mg, 0.75 mmol) in acetonitrile(10 ml) was treated with 1,1,1,3,3,3-hexamethyldisilazane (90 μl, 0.41mmol) and then heated at reflux for 2 h. The resulting gel-like mixturewas diluted with acetonitrile (5 ml) then treated withchloro(chloromethyl)-dimethylsilane (110 μl, 0.83 mmol) and heating atreflux continued for 24 h. The reaction was cooled, the acetonitrileremoved in vacuo and the residue treated with 1,2-dimethoxyethane (12ml). Caesium fluoride (160 mg, 1.4 mmol) was then added and the reactionheated at reflux for 6 h. After cooling to ambient temperature themixture was dissolved in 1:1 dichloromethane/methanol and pre-adsorbedonto silica. Purification by chromatography on silica eluting with 4%methanol in dichloromethane (containing 0.5% ammonia) followed by 8%methanol in dichloromethane (containing 0.5% ammonia) gave the titlecompound (65 mg, 25%): δ_(H) (400 MHz, DMSO) 3.47 (3H, s), 7.19 (1H, d,J 6), 7.57-7.88 (8H, m), 8.04 (1H, dd, J 8 and 1); m/z (ES⁺) 345 [M+H]⁺.

EXAMPLE 25′-(7-Ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-2′-fluorobiphenyl-2-carbonitrile

A suspension of2′-fluoro-5′-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile(50.0 mg, 0.51 mmol) in 1,2-dimethoxyethane (2 ml) andN,N-dimethylformamide (0.5 ml) was treated with sodium hydride (6.4 mgof a 60% dispersion in mineral oil, 0.16 mmol). After stirring atambient temperature for 10 min, lithium bromide (26.3 mg, 0.30 mmol) wasadded, and stirring continued for 15 min. Iodoethane (24.2 μl, 0.30mmol) was added and the solution heated at 65° C. for 18 h. Water (15ml) was added and the resulting mixture was extracted withdichloromethane (3×10 ml). The combined organic layers were washed withwater (10 ml), saturated sodium chloride solution (10 ml), dried overanhydrous magnesium sulphate then concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica gel, eluting with2% methanol in dichloromethane. Crystallisation from methanol affordedthe title compound as a white solid (23.9 mg, 44%): δ_(H) (500 MHz,CDCl₃) 1.38 (3H, t, J 7.2), 4.06 (2H, q, J 7.2), 6.72 (1H, d, J 5.9),7.39 (1H, t, J 9.3), 7.44 (1H, d, J 5.9), 7.53-7.61 (5H, m), 7.69-7.73(1H, m), 7.84 (1H, d, J 7.3); m/z (ES⁺) 359 [M+H]⁺.

Examples 3 and 4 are made by the method of Example 2 using1-bromo-2-fluoroethane and 2-bromo-1,1-difluoroethane respectively.

EXAMPLE 32′-Fluoro-5′-[7-(2-fluoroethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile

δ_(H) (500 MHz, CDCl₃) 4.27 (1H, t, J 4.5), 4.32 (1H, t, J 4.5), 4.71(1H, t, J 4.4), 4.81 (1H, t, J 4.5), 6.80 (1H, d, J 5.9), 7.40-7.43 (2H,m), 7.53-7.61 (4H, m), 7.63 (1H, s), 7.69-7.73 (1H, m), 7.85 (1H, d, J7.7); m/z (ES⁺) 377 [M+H]⁺.

EXAMPLE 45′-[7-(2,2-Difluoroethyl)-8-oxo-7,8-dihydroimidazo[1.2-a]pyrazin-3-yl]-2′-fluorobiphenyl-2-carbonitrile

δ_(H) (500 MHz, CDCl₃) 4.31 (2H, td, J 13 and 4.4), 6.14 (1H, tt, J 56and 4.4), 6.74 (1H, d, J 6.1), 7.41 (1H, t, J 9.3), 7.46 (1H, d, J 6.1),7.55-7.60 (4H, m), 7.65 (1H, s), 7.70-7.73 (1H, m), 7.85 (1H, d, J 7.1);m/z (ES⁺) 395 [M+H]⁺.

EXAMPLE 54,2′-Difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile

A suspension of 3-bromo-8-methoxyimidazo[1,2-a]pyrazine (1.6 g, 7 mmol)in hydrogen bromide (30 wt % in acetic acid, 15 ml) was heated at 80° C.for 90 min. The reaction was cooled, diluted with water (75 ml) thenneutralised with solid sodium hydrogencarbonate. The resulting solid wascollected by filtration, washed with water then dried under vacuum toafford 3-bromo-7H-imidazo[1,2-a]pyrazin-8-one as a white powder: δ_(H)(360 MHz, DMSO) 6.99 (1H, d, J 5.6), 7.29 (1H, d, J 5.6), 7.62 (1H, s).This powder was suspended in N,N-dimethylformamide (15 ml) then treatedwith sodium hydride (203 mg of a 60% dispersion in mineral oil, 8.4mmol). The resulting mixture was heated at 60° C. for 20 min thentreated with iodomethane (870 μl, 14 mmol). After stirring for 15 minthe reaction was cooled, diluted cautiously with water (150 ml) and thenextracted with dichloromethane (2×100 ml). The organics were combined,washed with water, dried over anhydrous magnesium sulphate, filtered andconcentrated under high vacuum. The residue was triturated with diethylether and the resulting solid collected by filtration to furnish3-bromo-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one as a white solid (1.4 g,88% over 2 steps): δ_(H) (360 MHz, DMSO) 3.45 (3H, s), 7.28 (1H, d, J6), 7.39 (1H, d, J 5.6), 7.62 (1H, s).

A mixture of the above product (171 mg, 0.76 mmol),4,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile(prepared as described in WO 02/074773) (392 mg, 1.2 mmol),palladium(II) acetate (7 mg, 0.03 mmol) and triphenylphosphine (8 mg,0.03 mmol) in 1,4-dioxane (3 ml) and 2M aqueous sodium carbonate (0.75ml) was heated at 80° C. for 3 h. The reaction was cooled then dilutedwith ethyl acetate (25 ml). The mixture was extracted with 4Nhydrochloric acid (25 ml) and the organics discarded. The aqueous waswashed with ethyl acetate, filtered through GF/A glass microfibre filterpaper and the filtrate made basic with solid sodium hydrogencarbonate.The resulting solid was collected by filtration, triturated with waterand dried under high vacuum to afford the title compound as acream-coloured solid (175 mg, 64%): δ_(H) (600 MHz, DMSO) 3.47 (3H, s),7.19 (1H, d, J 6.0), 7.57-7.61 (2H, m), 7.72 (1H, s), 7.76-7.86 (4H, m),8.08 (1H, dd, J 9 and 3); m/z (ES⁺) 363 [M+H]⁺.

Examples 6 to 11 were made by the method of Example 5.

EXAMPLE 64′-Fluoro-3′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile

4′-Fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile was coupled to give the titlecompound as an off-white solid (40 mg, 24%): δ_(H) (400 MHz, d₆-DMSO)3.48 (3H, s), 7.20 (1H, d, J 6), 7.43 (1H, dd, J 6 and 2), 7.61-7.66(2H, m), 7.72-7.86 (5H, m), 8.01 (1H, dd, J 8 and 1); m/z (ES⁺) 345[M+H]⁺.

EXAMPLE 75′-Fluoro-3′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile

5′-Fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrilewas coupled to give the title compound as an off-white solid (50 mg,29%): δ_(H) (400 MHz, d₆-DMSO) 3.48 (3H, s), 7.22 (1H, d, J 6),7.59-7.70 (5H, m), 7.79-7.87 (2H, m), 7.80 (1H, s), 8.03 (1H, dd, J 8and 1); m/z (ES⁺) 345 [M+H]⁺.

EXAMPLE 82,2′-Difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-4-carbonitrile

2,2′-Difluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-4-carbonitrile(prepared in the same way as in Example 19) was coupled to give thetitle compound as an off-white solid (30 mg, 16%): δ_(H) (400 MHz,d₆-DMSO) 3.48 (3H, a), 7.18 (1H, d, J 6), 7.59-7.61 (2H, m), 7.73 (1H,s), 7.75-7.82 (2H, m), 7.87-7.88 (2H, m), 8.05 (1H, d, J 10); m/z (ES⁺)363 [M+H]⁺.

EXAMPLE 97-Ethyl-3-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7H-imidazo[1,2-a]pyrazin-8-one

3-Bromo-7-ethyl-7H-imidazo[1,2-a]pyrazin-8-one and4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)benzeneboronic acidwere coupled to give the title compound as a white solid (43 mg, 23%):δ_(H) (400 MHz, d₆-DMSO) 1.26 (3H, t, J 7), 3.94 (3H, s), 3.96 (2H, s),5.52 (2H, s), 7.22-7.26 (2H, m), 7.44 (1H, dd, J 11 and 8), 7.65 (1H, d,J 6), 7.64 (1H, dd, J 8 and 2), 7.66 (1H, s), 7.98 (1H, s); m/z (ES⁺)369 [M+H]⁺.

EXAMPLE 106,2′-Difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile

6,2′-Difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrilewas coupled to produce the title compound: δ_(H) (400 Mz, CDCl₃) 3.59(3H, s), 6.71 (1H, d, J 6.0), 7.37-7.67 (8H, m); m/z (ES⁺) 363 [M+H]⁺.

EXAMPLE 114,2′-Difluoro-5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile

3-Bromo-7H-imidazo[1,2-a]pyrazin-8-one (prepared as described in Example5, 1.6 g, 7 mmol) was suspended in N,N-dimethylformamide (15 ml) thentreated with sodium hydride (420 mg of a 60% dispersion in mineral oil,10.5 mmol). The resulting mixture was heated at 60° C. for 20 min thentreated with iodoethane (840 μl, 10.6 mmol). After stirring for 40 minthe reaction was cooled, diluted cautiously with water (150 ml) and thenextracted with dichloromethane (2×100 ml). The organics were combined,washed with water, dried over anhydrous magnesium sulphate, filtered andconcentrated under high vacuum. The residue was triturated with diethylether and the resulting solid collected by filtration and recrystallizedfrom ethyl acetate/methanol to furnish3-bromo-7-ethyl-7H-imidazo[1,2-a]pyrazin-8-one as a white solid (0.34g): δ_(H) (400 MHz, DMSO) 1.23 (3H, t, J 7), 3.94 (2H, q, J 7), 7.31(1H, d, J 6), 7.41 (1H, d, J 6), 7.62 (1H, s); m/z (ES⁺) 244 and 242[M+H]⁺.

Reaction of the above product under the same Suzuki coupling conditionsas described in Example 5 gave the title compound afterrecrystallization from ethyl acetate/dichloromethane: δ_(H) (400 MHz,DMSO) 1.25 (3H, t, J 7.1), 3.96 (2H, q, J 7.1), 7.22 (1H, d, J 6.0),7.57-7.61 (2H, m), 7.72 (1H, s), 7.76-7.84 (4H, m), 8.07 (1H, dd, J 8.6and 2.7); m/z (ES⁺) 377 [M+H]⁺; Found C, 66.87; H, 3.54; N, 14.62.C₂₁H₁₄F₂N₄O requires C, 67.02; H, 3.75; N, 14.89%.

Examples 12 to 18 were prepared in the same way as Example 10.

EXAMPLE 124,2′-Difluoro-5′-[7-(2,2-difluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile

The title compound was prepared using 2-bromo-1,1-difluoroethane: δ_(H)(400 MHz, DMSO) 4.44 (2H, td, J 13 and 4.4), 6.36 (1H, tt, J 56 and4.4), 7.19 (1H, d, J 6.1), 7.60-7.65 (2H, m), 7.74-7.86 (5H, m), 8.08(1H, dd, J 8.6 and 2.7); m/z (ES⁺) 413 [M+H]⁺; Found C, 60.88; H, 2.97;N, 13.38. C₂₁H₁₂F₄N₄O requires C, 61.17; H, 2.93; N, 13.59%.

EXAMPLE 134,2′-Difluoro-5′-[7-(1-methylethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile

The title compound was prepared using 2-bromopropane: 85 (400 MHz, DMSO)1.33 (6H, d, J 6.8), 5.11 (1H, m), 7.20 (1H, d, J 6.1), 7.56-7.63 (2H,m), 7.74 (1H, m), 7.61-7.84 (4H, m), 8.06 (1H, dd, J 8.7 and 2.6); m/z(ES⁺) 391 [M+H]+; Found C, 68.00; H, 4.04; N, 14.03. C₂₂H₁₆F₄N₄Orequires C, 67.79; H, 4.13; N, 14.35%.

EXAMPLE 144,2′-Difluoro-5′-[7-(2-fluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile

The title compound was prepared using 1-bromo-2-fluoroethane instead ofiodoethane: δ_(H) (400 MHz, DMSO) 4.25 (1H, t, J 4.5), 4.31 (1H, t, J4.5), 4.65 (1H, t, J 4.5), 4.77 (1H, t, J 4.5), 7.18 (1H, d, J 6.0),7.59-7.62 (2H, m), 7.74 (1H, m), 7.75-7.85 (4H, m), 8.07 (1H, dd, J 8.7and 2.6); m/z (ES⁺) 395 [M+H]⁺; Found C, 63.49; H, 3.27; N, 13.96.C₂₁H₁₃F₃N₄O requires C, 63.96; H, 3.32; N, 14.21%.

EXAMPLE 154,2′-Difluoro-5′-[7-(2,2,2-trifluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile

The title compound was prepared using 1-iodo-2,2,2-trifluoroethane:δ_(H) (400 MHz, DMSO) 4.90 (2H, q, J 9.2), 7.20 (1H, d, J 6.0),7.60-7.66 (2H, m), 7.75-7.85 (5H, m), 8.06 (1H, dd, J 8.7 and 2.6); m/z(ES⁺) 431 [M+H]⁺.

EXAMPLE 164,2′-Difluoro-5′-[7-(2-methyl-2H-[1,2,4]triazol-3-ylmethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile

The title compound was prepared using3-chloromethyl-2-methyl-2H-[1,2,4]triazole: δ_(H) (400 MHz, DMSO) 3.96(3H, s), 5.35 (2H, s), 7.28 (1H, d, J 6.0), 7.62-7.64 (2H, m), 7.75-7.84(6H, m), 8.06 (1H, dd, J 8.6 and 2.7); m/z (ES⁺) 444 [M+H]⁺; Found C,62.48; H, 3.67; N, 21.98. C₂₃H₁₅F₂N₇O requires C, 62.30; H, 3.41; N,22.11%.

EXAMPLE 174,2′-Difluoro-5′-[8-oxo-7-(pyridin-2-ylmethyl)-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

The title compound was prepared using 2-chloromethylpyridinehydrochloride: δ_(H) (400 MHz, DMSO) 5.26 (2H, s), 7.28-7.35 (3H, m),7.61-7.63 (2H, m), 7.76-7.86 (6H, m), 8.06 (1H, dd, J 8.6 and 2.7), 8.50(1H, m); m/z (ES⁺) 440 [M+H⁺; Found C, 68.19; H, 3.48; N, 15.69.C₂₆H₁₅F₂N₅O requires C, 68.33; H, 3.44; N, 15.94%.

EXAMPLE 186,2′-Difluoro-5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile

This compound was prepared using6,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrilein the final step: δ_(H) (400 MHz, CDCl₃) 1.38 (3H, t, J 7.1), 4.04 (2H,q, J 7.1), 6.72 (1H, d, J 6.0), 7.38-7.67 (8H, m); m/z (ES⁺) 377 [M+H]⁺.

EXAMPLE 193-Chloro-2′-fluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-4-carbonitrile

A mixture of 4-bromo-2-chlorobenzonitrile (2.2 g, 10 mmol) and2-fluorobenzeneboronic acid (1.82 g, 13 mmol) in tetrahydrofuran (30 ml)was treated with 2M sodium carbonate (13 ml) then degassed with nitrogenfor 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol)was added and this mixture was heated under reflux for 12 h. Theresulting mixture was partitioned between dichloromethane and water. Theorganics were washed with water, brine, dried over anhydrous magnesiumsulphate, filtered and concentrated in vacuo. Purification of theresidue by chromatography on silica gel eluting with isohexane on agradient of ethyl acetate (5-15%) gave3-chloro-2′-fluorobiphenyl-4-carbonitrile as a white solid (2.3 g, 99%):δ_(H) (400 MHz, CDCl₃) 7.17-7.57 (5H, m), 7.64-7.75 (2H, m).

To a slurry of the above product (2.3 g, 10 mmol) and1,3-dibromo-5,5-dimethylhydantoin (3.1 g, 11 mmol) in acetonitrile (20ml) was added concentrated sulphuric acid (0.8 ml). The slurry waswarmed to 70° C. and the resulting solution stirred at 70° C. for 16 h.After 16 h, the reaction was complete. Water (75 ml) was added and theresulting suspension was filtered and dried, to give5′-bromo-3-chloro-2′-fluorobiphenyl-4-carbonitrile as an off-white solid(3.1 g, 98%): δ_(H) (360 MHz, CDCl₃) 7.07-7.17 (1H, m), 7.29-7.76 (5H,m).

The above product (0.6 g, 2 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi{[1,3,2]dioxaborolanyl} (0.6 g,2.4 mmol) and potassium acetate (0.39 g, 4 mmol) were suspended in1,4-dioxane (6 ml) and the mixture was degassed with nitrogen for 10minutes, before adding1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) complex withdichloromethane (0.05 g, 0.06 mmol). The resulting mixture was heated at90° C. for 12 h. The mixture was cooled to ambient temperature, filteredand the filter-cake washed with dichloromethane. The filtrate wasevaporated to dryness and the residue stirred with ice-cold 2N sodiumhydroxide (70 ml) for 20 minutes. The aqueous mixture was filtered andthe filtrate washed with diethyl ether (2×50 ml). The organics werediscarded and the aqueous phase cooled to 0° C. before lowering the pHto 6 by addition of 36% hydrochloric acid. The product was extractedinto diethyl ether to give3-chloro-2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-4-carbonitrileas a yellow oil (0.53 g, 74%).

3-Bromo-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one and the above productwere coupled in the same way as in Example 5 to give the title compoundas an off-white solid (50 mg, 26%): δ_(H) (360 MHz, d₆-DMSO) 3.48 (3H,s), 7.18 (1H, d, J 6), 7.56-7.59 (2H, m), 7.70-7.90 (2H, m), 8.12 (2H,dd, J 8 and 3); m/z (ES⁺) 379 [M+H]⁺.

EXAMPLE 203-[4-Fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one

A cooled (−20° C.) solution of 2,2,6,6-tetramethylpiperidine (28 ml, 165mmol) in tetrahydrofuran (400 ml) was treated with n-butyllithium (63 mlof a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooledto −78° C. 1-Bromo-4-fluorobenzene (16.5 ml, 150 mmol) was then addedneat and dropwise over 10 min and stirring at −78° C. was continued for3 h. Triisopropyl borate (40 ml, 172.5 mmol) was then added and stirringat −78° C. continued for 30 min before removing the cooling bath. Whenthe internal temperature of the reaction reached −40° C., 5Nhydrochloric acid was added (75 ml) and the mixture was stirred toambient temperature. After stirring at ambient temp for 1 h the majorityof the tetrahydrofuran was removed and the mixture partitioned betweenether (500 ml) and 1N hydrochloric acid (500 ml). The organics were thenextracted with 2N sodium hydroxide (400 ml) and the organics werediscarded. The aqueous was cooled in an ice-water bath and 5Nhydrochloric acid (150 ml) was added dropwise over 15 min. The resultingwhite solid was collected and dried under vacuum to afford5-bromo-2-fluorobenzeneboronic acid (25 g, 76%).

A solution of the above product (25 g, 114 mmol) in tetrahydrofuran wastreated with hydrogen peroxide (7.8 ml of a 35 wt % solution in water)then with sodium hydroxide (1.4 ml of a 4N solution in water). A mildexotherm caused the internal temperature to reach 40° C. This mixturewas left to stir at ambient temperature for 14 h then treated withmanganese dioxide (200 mg) and stirring was continued for 90 min beforefiltering the reaction (GF/A filter paper). The filtrate wasconcentrated on a rotary evaporator and the residue partitioned betweenether (400 ml) and water. The organics were washed with more water,brine and dried over anhydrous magnesium sulphate. Filtration andevaporation to dryness afforded 5-bromo-2-fluorophenol (19.7 g, 90%) asa colourless liquid: δ_(H) (400 MHz, d₆-DMSO) 6.93-6.97 (1H, m),7.09-7.14 (2H, m), 10.36 (1H, br).

An ice-cooled solution of the above product (1.91 g, 10 mmol),(1-methyl-1H-[1,2,3]triazol-4-yl)methanol (1.24 g, 11 mmol) andtriphenylphosphine (3.93 g, 15 mmol) in tetrahydrofuran (50 ml) wastreated dropwise with diisopropyl azodicarboxylate (3.03 g, 15 mmol)over 10 min. The resulting mixture was stirred to ambient temperatureover 12 h and then glacial acetic acid (1 ml) was added. The reactionmixture was concentrated in vacuo then partitioned between ethyl acetateand 0.01N sodium hydroxide solution. The organics were washed withwater, brine, dried over anhydrous magnesium sulphate and concentratedto give an oil. This oil was purified by chromatography on silica geleluting with isohexane on a gradient of ethyl acetate (20-50%).Product-containing fractions were concentrated and the resulting residuetriturated with 10% ether in isohexane to furnish4-(5-bromo-2-fluorophenoxymethyl)-1-methyl-1H-[1,2,3]triazole as a whitesolid (1.9 g, 66%): δ_(H) (360 MHz, d₆-DMSO) 4.06 (3H, s), 5.25 (2H, s),7.10-7.20 (2H, m), 7.55-7.70 (1H, m), 8.19 (1H, s).

The above product was converted to4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)-benzeneboronic acidas described in Example 19: δ_(H) (400 MHz, d₆-DMSO) 4.06 (3H, s), 5.19(2H, s), 7.16 (1H, dd, J 12 and 8), 7.38-7.41 (1H, m), 7.71 (1H, dd, J 9and 1), 8.09 (2H, s), 8.16 (1H, s).

The above product was coupled as described in Example 5 to afford thetitle compound as a white solid: δ_(H) (400 MHz, d₆-DMSO) 3.48 (3H, s),4.06 (3H, s), 5.35 (2H, s), 7.17-7.21 (2H, m), 7.39 (1H, dd, J 11 and8), 7.55 (1H, d, J 6), 7.60 (1H, dd, J 8 and 2), 7.67 (1H, s), 8.22 (1H,s); m/z (ES⁺) 355 [M+H]⁺.

EXAMPLE 213-[4-Fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one

A cooled (0° C.) solution of 5-bromo-2-fluorophenol,(2-methyl-2H-[1,2,4]triazol-3-yl)methanol and triphenylphosphine intetrahydrofuran was treated dropwise with diisopropyl azodicarboxylateover 10 min. The resulting mixture was stirred overnight and then aceticacid was added. The reaction mixture was evaporated to dryness and theresidue was partitioned between ethyl acetate and 0.01N sodium hydroxidesolution. The organic phase was washed with water and brine, dried overanhydrous magnesium sulphate and pre-adsorbed onto silica. Purificationby flash column chromatography on silica gel, eluting with isohexane ona gradient of ethyl acetate (10-50%), led to product-containingfractions that were combined. The material was further purified by flashcolumn chromatography on silica gel, eluting with dichloromethanecontaining 1% ammonia on a gradient of methanol (0.5-3%), to give5-(5-bromo-2-fluoro-phenoxymethyl)-1-methyl-1H-[1,2,4]triazole as anoff-white solid (2.1 g, 37%): δ_(H) (360 MHz, CDCl₃) 4.01 (3H, s), 5.29(2H, s), 6.96-6.99 (1H, m), 7.09-7.13 (1H, m), 7.29 (1H, dd, J 5 and 2),7.88 (1H, s); m/z (ES⁺) 288 [MH⁺].

The above product was reacted with4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi{[1,3,2]-dioxaborolanyl} asdescribed in Example 19 to give the title compound as a pale yellowsolid (0.43 g, 62%).

The above product was coupled in the same way as in Example 5 to givethe title compound as a white solid (58 mg, 33%): δ_(H) (400 MHz,d₆-DMSO) 3.48 (3H, s), 3.94 (3H, s), 5.52 (2H, s), 7.21-7.25 (2H, m),7.45 (1H, dd, J 11 and 8), 7.53 (1H, d, J 6), 7.62 (1H, dd, J 8 and 2),7.65 (1H, s), 7.98 (1H, s); m/z (ES⁺) 355 [M+H]⁺.

EXAMPLE 224,2′-Difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

A suspension of 8-chloroimidazo[1,2-a]pyrazine (5 g, 325 mmol) in 5Nhydrochloric acid (35 ml) was heated at 90° C. for 14 h. The reactionmixture was cooled, then concentrated using rotary evaporation.Azeotropic removal of water with toluene (2×30 ml) gave8-oxo-7,8-dihydroimidazo[1,2-a]pyrazine hydrochloride (5.7 g): δ_(H)(360 MHz, DMSO) 7.01 (1H, d, J 5.6), 7.60 (1H, d, J 5.6), 7.70 (1H, s),7.97 (1H, s), 11.59 (1H, br s).

The above product (1 g) was suspended in N,N-dimethylformamide (15 ml)then treated with sodium hydride (650 mg of a 60% dispersion in mineraloil). The resulting mixture was heated at 60° C. for 20 min then cooledto room temperature and treated with iodomethane (0.4 ml). Afterstirring for 15 h the reaction mixture was diluted cautiously withmethanol (5 ml) and then silica gel (5 g) was added and the solventsremoved under vacuum. The silica residue was filtered through a plug ofsilica gel, using 10% methanol in dichloromethane as eluent, then thesolvents were removed in vacuo to leave7-methyl-7H-imidazo[1,2-a]pyrazin-8-one (1.15 g): δ_(H) (360 MHz, DMSO)3.43 (3H, s), 7.11 (1H, d, J 5.8), 7.46 (1H, s), 7.56 (1H, d, J 5.8),7.78 (1H, s). NOE studies showed that irradiation of the 3H singlet at δ3.43 gave enhancement of the doublet at δ 7.11 and vice-versa indicatingthat methylation took place on the 7-nitrogen rather than the 8-oxygen.

The above product (315 mg, 2.1 mmol) in a Parr flask was dissolved inmethanol (20 ml) and 10% Pd—C catalyst (100 mg) was added. The reactionmixture was shaken under 55 psi of hydrogen for 16 days then filteredand concentrated under vacuum to leave a residue. This wasrecrystallized from ethyl acetate/methanol to give7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (185 mg): δ_(H)(360 MHz, DMSO) 3.31 (3H, s), 3.70-3.73 (2H, m), 4.24-4.28 (2H, m), 7.08(1H, s), 7.32 (1H, s).

The above product (80 mg, 0.53 mmol) and5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared as described inWO 02/074773, 204 mg, 1.3 mol eq) were dissolved in DMA (2 ml) andpotassium acetate (280 mg, 1.5 mol eq), palladium acetate (6 mg, 5 mol%) and triphenylphosphine (7 mg, 5 mol %) were all added. After bubblingnitrogen through the reaction mixture for 10 min, the temperature wasraised to 130° C. and heating continued for 3 h. After cooling, thecrude reaction mixture was poured onto a column of silica and purifiedusing 0-5% methanol in dichloromethane as eluent. Recrystallization fromethyl acetate/dichloromethane gave the title compound (18 mg), mp 224°C.: δ_(H) (400 MHz, DMSO) 3.02 (3H, s), 3.72-3.75 (2H, m), 4.35-4.38(2H, m), 7.38 (1H, s), 7.57 (1H, m), 7.72-7.78 (4H, m), 8.06 (1H, dd, J9 and 3); m/z (ES⁺) 365 [M+H]⁺.

Examples 23 and 24 were prepared by the method of Example 22:

EXAMPLE 235,2′-Difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

The title compound was prepared using5′-bromo-5,2′-difuorobiphenyl-2-carbonitrile in the final step: δ_(H)(400 MHz, CDCl₃) 3.18 (3H, s), 3.75-3.77 (2H, m), 4.32-4.34 (2H, m),7.24-7.28 (1H, m), 7.30-7.38 (3H, m), 7.44-7.46 (1H, m), 7.52-7.55 (1H,m), 7.83 (1H, dd, J 7 and 4); m/z (ES⁺) 365 [M+H]⁺.

EXAMPLE 246,2′-Difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

The title compound was prepared using5′-bromo-6,2′-difluorobiphenyl-2-carbonitrile in the final step: δ_(H)(400 MHz, CDCl₃) 3.19 (3H, s), 3.73-3.78 (2H, m), 4.28-4.35 (2H, m),7.34-7.42 (3H, m), 7.45-7.49 (1H, m), 7.54-7.58 (2H, m), 7.64 (1H, m);m/z (ES⁺) 365 [M+H]⁺.

EXAMPLE 254,2′-Difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

8-Oxo-7,8-dihydroimidazo[1,2-a]pyrazine hydrochloride (see Example 20, 1g) in a Parr flask was dissolved in methanol (60 ml) and 10% Pd—Ccatalyst (300 mg) was added. The reaction mixture was shaken under 55psi of hydrogen for 17 days then filtered and concentrated under vacuumto leave a residue. This was recrystallized from ethyl acetate/methanolto give 8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride(610 mg): δ_(H) (360 MHz, DMSO) 3.66-3.70 (2H, m), 4.36-4.39 (2H, m),7.67 (1H, s), 7.78 (1H, s), 8.84 (1H, br s).

The above product (500 mg, 40 mmol) was suspended inN,N-dimethylformamide (10 ml) then treated with sodium hydride (380 mgof a 60% dispersion in mineral oil, 2.4 mol eq). The resulting mixturewas heated at 60° C. for 20 min then cooled to room temperature andtreated with iodoethane (0.386 ml, 1.2 mol eq). After stirring for 15 hthe reaction mixture was diluted cautiously with methanol (5 ml) andthen silica gel (4 g) was added and the solvents removed under vacuum.The silica residue was filtered through a plug of silica gel, using 10%methanol in dichloromethane as eluent, then the solvents were removed invacuo to leave 7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine(400 mg): δ_(H) (400 MHz, DMSO) 1.10 (3H, t, J 7.2), 3.47 (2H, J 7.2),3.70-3.73 (2H, m), 4.23-4.27 (2H, m), 7.08 (1H, s), 7.32 (1H, s).

The above product (82.5 mg, 0.53 mmol) and5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared as described inWO 02/074773, 204 mg, 1.3 mol eq) were dissolved in DMA (2 ml) andpotassium acetate (280 mg, 1.5 mol eq), palladium acetate (6 mg, 5 mol%) and triphenylphosphine (7 mg, 5 mol %) were all added. After bubblingnitrogen through the reaction mixture for 10 min, the temperature wasraised to 130° C. and heating continued for 3 h. After cooling, thecrude reaction mixture was poured onto a column of silica and purifiedusing 0-5% methanol in dichloromethane as eluent. Recrystallation fromethyl acetate/dichloromethane gave the title compound (18 mg): δ_(H)(400 MHz, DMSO) 1.12 (3H, t, J 7.1), 3.51 (2H, q, J 7.1), 3.73-3.76 (2H,m), 4.34-4.37 (2H, m), 7.39 (1H, s), 7.57 (1H, m), 7.72-7.78 (4H, m),8.06 (1H, dd, J 9 and 3); m/z (ES⁺) 379 [M+H]⁺.

Examples 26 to 28 were prepared using the method of Example 25 using5′-bromo-5,2′-difluorobiphenyl-2-carbonitrile and5′-bromo-6,2′-difluorobiphenyl-2-carbonitrile respectively (prepared asdescribed in WO 02/074773):

EXAMPLE 265,2′-Difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

This compound was prepared using5′-bromo-5,2′-difluorobiphenyl-2-carbonitrile (prepared as described inWO 02/074773): δ_(H) (400 MHz, DMSO) 1.11 (3H, t, J 7.1), 3.51 (2H, q, J7.1), 3.73-3.76 (2H, m), 4.35-4.38 (2H, m), 7.40 (1H, s), 7.55-7.61 (2H,m), 7.68-7.78 (3H, m), 8.13 (1H, dd, J 9 and 3); m/z (ES⁺) 379 [M+H]⁺.

EXAMPLE 276,2′-Difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

δ_(H) (400 MHz, DMSO) 1.20 (3H, t, J 7.1), 3.59 (2H, q, J 7.1),3.82-3.85 (2H, m), 4.39-4.45 (2H, m), 7.45 (1H, s), 7.65-7.70 (1H, m),7.83-7.92 (4H, m), 8.00 (1H, dd, J 9 and 3); m/z (ES⁺) 379 [M+H]⁺.

EXAMPLE 284,2′-Difluoro-5′-[8-oxo-7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile

8-Oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (87 mg,0.53 mmol), prepared as described in Example 25, was reacted with5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared as described inWO 02/074773, 204 mg, 1.3 mol eq) in DMA (2 ml) in the presence ofpotassium acetate (280 mg, 1.5 mol eq), palladium acetate (6 mg, 5 mol%) and triphenylphosphine (7 mg, 5 mol %). After bubbling nitrogenthrough the reaction mixture for 10 min, the temperature was raised to130° C. and heating continued for 3 h. After cooling, the crude reactionmixture was poured onto a column of silica and purified using 0-5%methanol in dichloromethane as eluent. Recrystallization from ethylacetate/dichloromethane gave4,2′-difluoro-5′-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile(126 mg): δ_(H) (400 MHz, DMSO) 3.54-3.58 (2H, m), 4.28-4.32 (2H, m),7.39 (1H, s), 7.54-7.59 (1H, m), 7.71-7.78 (4H, m), 8.05-8.08 (1H, m),8.18 (1H, br s); m/z (ES⁺) 351 [M+H]⁺.

The title compound was prepared using the method described in the firstpart of Example 11, using 2-chloromethylpyridine hydrochloride: δ_(H)(400 MHz, DMSO) 3.60-3.64 (2H, m), 4.18-4.22 (2H, m), 4.60 (2H, m),7.08-7.11 (1H, m), 7.16-7.19 (1H, m), 7.21 (1H, s), 7.54-7.59 (1H, m),7.52-7.56 (5H, m), 7.82-7.86 (1H, m), 8.30-8.32 (1H, m); m/z (ES⁺) 442[M+H]⁺.

EXAMPLE 294,2′-Difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-d][1,2,4]triazin-3-yl)biphenyl-2-carbonitrile

2-Hydrazinocarbonylimidazole (prepared according to the proceduredescribed in EP-A-0713876) (1.00 g, 7.93 mmol) was suspended in DowthermA (6 ml), N,N-dimethylformamide dimethyl acetal (1.89 g, 15.9 mmol)added and the mixture heated at 100° C. for 1.5 h then at 210° C. for 18h. The mixture was allowed to cool to room temperature, diethyl ether(100 ml) added and the precipitated solid was filtered. The brown solidwas purified by dry flash column chromatography on silica eluting withdichloromethane (+0.1% 0.880 ammonia) on a gradient of methanol (5-12%).Collecting appropriate fractions gave7H-imidazo[1,2-d][1,2,4]triazin-8-one (216 mg, 20%) as an off-whitesolid: δ_(H) (400 MHz, CDCl₃) 7.59 (1H, d, J 1), 7.91 (1H, d, J 1), 8.74(1H, s), 12.39 (1H, s).

Sodium hydride (60% suspension in mineral oil) (76 mg, 1.90 mmol) wasadded to a suspension of the above product (216 mg, 1.59 mmol) inN,N-dimethylformamide (4 ml) and the mixture stirred at 20° C. for 10min then at 60° C. for 5 min. The mixture was allowed to cool to ambienttemperature, methyl iodide (676 mg, 4.76 mmol) added and the mixtureleft to stir for 10 min. The solvent was evaporated and the residue waspurified by flash column chromatography on silica eluting withdichloromethane on a gradient of methanol (2-4%). Collecting appropriatefractions gave 7-methyl-7H-imidazo[1,2-d][1,2,4]triazin-8-one (150 mg,63%) as a pale yellow solid: δ_(H) (360 MHz, CDCl₃) 7.45 (1H, d, J 1),7.63 (1H, d, J 1), 8.19 (1H, s).

The above product (75 mg, 0.50 mmol),5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared according to theprocedure described in WO 02/38568) (220 mg, 0.75 mmol) and potassiumacetate (74 mg, 0.75 Mmol) were suspended in N,N-dimethylacetamide (2ml) and degassed with nitrogen for 10 min. Palladium(II) acetate (5.6mg, 0.025 mmol) and triphenylphosphine (6.6 mg, 0.025 mmol) were addedand the mixture heated at 130° C. for 2 h. The mixture was allowed tocool to ambient temperature, diluted with ethyl acetate (100 ml) andwashed with water (50 ml) and brine (50 ml), dried over anhydrous sodiumsulfate, filtered and evaporated to give a yellow solid. The solid waspurified by flash column chromatography on silica eluting with 2%methanol in dichloromethane. Collecting appropriate fractions followedby trituration with diethyl ether gave the title compound as a whitesolid: δ_(H) (400 MHz, CDCl₃) 3.80 (3H, s), 7.41-7.47 (2H, m), 7.53-7.64(4H, m), 7.67 (1H, s), 8.42 (1H, s); m/z (ES⁺) 364 (M⁺+H).

EXAMPLE 303′-(1-Methyl-6-oxo-1,6-dihydropurin-9-yl)biphenyl-2-carbonitrile

Sodium methoxide (2.70 g, 50.0 mmol) was added portionwise over 10 minto a 0° C. suspension of 4,6-dichloro-5-nitropyrimidine (4.85 g, 25.0mmol) in methanol (90 ml). On complete addition the mixture was stirredat 0° C for 2 h. The precipitate was filtered and the filtrateevaporated. The residue was suspended in isohexane and filtered. Thefiltrate was evaporated and the residue purified by flash columnchromatography on silica, eluting with 5% ethyl acetate in isohexane.Collecting appropriate fractions gave4-chloro-6-methoxy-5-nitropyrimidine (3.50 g, 74%) as a white solid:δ_(H) (400 MHz, CDCl₃) 4.15 (3H, s), 8.65 (1H, s).

The above product (3.50 g, 18.5 mmol) and3′-aminobiphenyl-2-carbonitrile (prepared according to the proceduredescribed in WO 02/38568) (3.23 g, 16.6 mmol) were dissolved intriethylamine (9.32 g, 92.3 mmol) and dimethylsulfoxide (10 ml) andheated at 90° C. for 18 h. The mixture was allowed to cool to ambienttemperature then poured onto water (150 ml) and extracted with ethylacetate (2×300 ml). The organic fractions were combined, washed withwater (3×75 ml) and brine (50 ml), dried over anhydrous sodium sulfate,filtered and evaporated to give a brown solid. The brown solid wastriturated with diethyl ether (50 ml), filtered, washed with diethylether (2×10 ml) and left to air dry, which gave3′-(1-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-4-ylamino)biphenyl-2-carbonitrile(2.24 g, 38%) as a yellow solid: δ_(H) (360 MHz, CDCl₃) 3.52 (3H, s),7.45-7.57 (5H, m), 7.68 (1H, ddd, J 8, 8 and 1), 7.78-7.82 (2H, m), 8.04(1H, s), 11.13 (1H, s).

The above product (100 mg, 0.28 mmol) was suspended in THF (5 ml) andethanol (5 ml), tin(II) chloride (162 mg, 0.72 mmol) added and themixture heated under reflux for 18 h. The solvent was evaporated and theresidue suspended in formic acid (20 ml) and heated under reflux for 48h. The mixture was allowed to cool to ambient temperature and thesolvent evaporated. The residue was dissolved in dichloromethane andmethanol and evaporated onto silica. The product was purified by flashcolumn chromatography on the same, eluting with dichloromethane (+0.1%0.880 ammonia) on a gradient of methanol (2-5%). Collecting appropriatefractions gave the title compound (35 mg, 37%) as a white solid: δ_(H)(500 MHz, DMSO) 3.55 (3H, s), 7.65 (1H, dd, J 8 and 8), 7.72-7.79 (3H,m), 7.85 (1H, ddd, J 8, 8 and 1), 7.97 (1H, dd, J 8 and 1), 8.00-8.04(2H, m), 8.45 (1H, s), 8.59 (1H, s); m/z (ES⁺) 328 (M⁺+H).

1. A compound of the formula I:

wherein: —U—V— represents —CH═CH—, or —CH₂—CH₂—; X¹ represents hydrogen,halogen, C₁₋₆ alkyl, trifluoromethyl or C₁₋₆ alkoxy; X² representshydrogen or halogen; Y represents a chemical bond; Z represents asubstituted phenyl or triazolyl group, wherein the substituent isselected from fluoro, chloro, cyano, nitro, methyl, hydroxy, methoxy,oxy, methanesulphonyl, amino, aminocarbonyl, formyl, methoxycarbonyl and—CH═NOH; R¹ represents C₁₋₆ alkyl, halo(C₁₋₆)alkyl,methyl-triazolylmethyl or pyridinylmethyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein —U—V—represents —CH═CH—.
 3. The compound of claim 1 wherein R¹ is methyl,ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, isopropyl,methyl-triazolylmethyl or pyridinylmethyl.
 4. The compound of claim 1wherein X¹ is fluorine and X² is hydrogen.
 5. The compound of claim 1wherein Z is a substituted phenyl or triazolyl group, wherein thesubstituent is selected from fluoro, chloro, cyano and methyl.
 6. Acompound of claim 1, which is selected from the group consisting of:2′-fluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-2′-fluorobiphenyl-2-carbonitrile;2′-fluoro-5′-[7-(2-fluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;5′-[7-(2,2-difluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]-2′-fluorobiphenyl-2-carbonitrile;4,2′-difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;4,2′-difluoro-5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;4,2′-difluoro-5′-[7-(2,2-difluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;4,2′-difluoro-5′-[7-(1-methylethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;3-chloro-2′-fluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-4-carbonitrile;4,2′-difluoro-5′-[7-(2-fluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;4′-fluoro-3′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;5′-fluoro-3′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;2,2′-difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-4-carbonitrile;4,2′-difluoro-5′-[7-(2,2,2-trifluoroethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl]biphenyl-2-carbonitrile;4,2′-difluoro-5′-[7-(2-methyl-2H-[1,2,4]triazol-3-ylmethyl)-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yllbiphenyl-2-carbonitrile;3-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one;3 -[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7-methyl-7H-imidazo[1,2-a]pyrazin-8-one;7-ethyl-3-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-7H-imidazo[1,2-a]pyrazin-8-one;4,2′-difluoro-5′-[8-oxo-7-(pyridin-2-ylmethyl)-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;4,2′-difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;4,2′-difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;5,2′-difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;6,2′-difluoro-5′-(7-ethyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;6,2′-difluoro-5′-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;6,2′-difluoro-5′-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-biphenyl-2-carbonitrile;5,2′-difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;4,2′-difluoro-5′-[8-oxo-7-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;6,2′-difluoro-5′-(7-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile;or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable exicipient.8. A pharmaceutical composition comprising the compound of claim 6 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable exicipient.